"What's needed is a drug that reduces the risk of forming large clots but still allows you to form a clot when you need one to stanch bleeding," Alisa Wolberg says. "The biological pathway we've discovered may make it possible to strike that balance." (Credit: iStockphoto)

A safer way to shrink deadly blood clots

Researchers have discovered a way to shrink dangerous blood clots by 50 percent. They say it might offer a safer alternative to blood thinners.

Experiments with mice and human blood focused on the role of an enzyme known as factor XIII. Mice without the enzyme had much smaller clots compared to normal mice.

The discovery could have major implications for people at high risk of deep vein thrombosis (DVT), a condition that—together with its deadly cousin pulmonary embolism—kills as many as 100,000 people every year in the United States.

“If we can develop a treatment that exploits this discovery to reduce the size of blood clots, it would represent a whole new approach to treating thrombosis that’s different from anything else on the market,” says Alisa Wolberg, associate professor of pathology and laboratory medicine at the University of North Carolina at Chapel Hill and senior author of the paper published in the Journal of Clinical Investigation.

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“We think reducing factor XIII activity could be helpful to a large number of people, perhaps including some who cannot take existing ‘blood-thinning’ medications,” adds Wolberg.

In patients with DVT, clots that form inside blood vessels, usually in the legs, obstruct the flow of blood, leading to pain and swelling while raising the risk of pulmonary embolism—a life-threatening condition in which a clot breaks away, travels through the bloodstream, and obstructs a crucial artery in the lungs.

DVT often occurs during periods of restricted movement, such as prolonged sitting common during a long trip. Also, pregnancy, cancer, genetics, certain kinds of injuries, surgeries, and medications can raise the risk of developing DVT.

Many patients at high risk for developing clots regularly take blood-thinning drugs, such as warfarin, which stifles the body’s ability to make fibrin—the fibrous protein that binds a clot together. But these drugs can raise the risk of excessive bleeding, can cause side effects, and aren’t appropriate for all patients.

“What’s needed is a drug that reduces the risk of forming large clots but still allows you to form a clot when you need one to stanch bleeding,” Wolberg says. “The biological pathway we’ve discovered may make it possible to strike that balance.”

‘We knew we had found something new’

The researchers were surprised when they found that mice incapable of producing factor XIII formed clots that were half the size of the clots produced by normal mice.

“That difference in itself was extremely striking,” says Maria Aleman, first author of the paper and a graduate student in Wolberg’s lab at the time of the study. “Then, the second surprise was discovering that the size difference was actually due to a reduced number of red blood cells in the clot.

“Since no previous studies had suggested that it was possible to manipulate the number of red blood cells, we knew we had found something new.”

Factor XIII appears to play a crucial role in helping the fibrin matrix keep its integrity during clot formation. Normally, the fibrin matrix forms a strong mesh in and around the clot, trapping red blood cells within. Without factor XIII, some red blood cells are squeezed out, resulting in a much smaller clot.

Unlike existing drugs that reduce the formation of fibrin, a drug that reduces factor XIII could potentially cut the body’s ability to produce large, dangerous clots without sacrificing the ability to produce small, beneficial clots.

Such a drug, then, would benefit patients at risk of developing the most dangerous kinds of clots.

Additional researcher from UNC, Emory University, the Georgia Institute of Technology, the University of Colorado at Denver, and the Cincinnati Children’s Hospital Medical Center collaborated on the study, which was funded by the National Institutes of Health and the American Heart Association.